(4R-cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluoro-phenyl)-5-(1-methyl-ethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]dioxane-4-yl-acetic acid-tertiary butyl ester of the Formula I was described in EP-B 330,172. According to said patent (4R-cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluoro-phenyl)-5-(1-methyl-ethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]dioxane-4-yl-acetic acid-tertiary butyl ester of the Formula I is prepared by reacting (4R-cis)-1,1-dimethyl-ethyl-6-(2-amino-ethyl)-2,2-dimethyl-1,3-dioxane-4-acetate of the Formula
with 2-[1-phenyl-2-(4-fluoro-phenyl)-2-oxo-ethyl]-4-methyl-N-methyl-N-phenyl-3-oxo-pentanamide of the Formula
in a 9:1 mixture of heptane and toluene under heating to boiling for 24 hours, cooling the reaction mixture, adding some 2-propanol and isolating the precipitated product by filtration. The reference is silent in disclosing the melting point of the product and the crystal form of the product is not mentioned either.
According to U.S. Pat. No. 5,103,024 the reaction is carried out as described in EP-B 330,172 except that a 9:1 mixture of toluene and heptane is used; the reaction mixture is then heated to boiling for 24 hours, cooled, some 2-propanol is added and the precipitated compound of the Formula I is isolated by filtration. Nothing is disclosed about the melting point and crystal form is the product.
In U.S. Pat. No. 5,155,251 the working example of EP-B 330,172 is disclosed. This reference contains no teaching on the melting point and crystal form of the compound of the Formula I.
According to Tetrahedron Letters Vol. 33. Np. 17, 2283-2284 (1992) the reaction of the compounds of the Formulae II and III is carried out in a 1:4:1 mixture of toluene, heptane and tetrahydrofurane in the presence of pivalic acid as catalyst. The isolation of the product from the reaction mixture is not described, nor is it disclosed whether the compound of the Formula I is formed in solid form.
Recently a strong demand has arisen for pure and morphologically uniform products. Technological procedures more and more require products which possess constant, stable and identical filtration and drying properties. Because of economical reasons there is a need for morphologically uniform products which can be prepared by methods readily feasible on industrial scale, suitable for scaling-up and providing a product of constantly identical crystalline form.
It is known that amorphous products can be difficultly filtered and dried, the scaling-up of the manufacturing process is encountered with considerable difficulties and the stability of the product is not satisfactory either.